The overall goal of this project is to define the molecular events involved in the transformation of low-grade lymphomas to more aggressive forms. As a first approach, we have studied a series of recurrent follicular lymphomas to assess the status of their immunoglobulin and bcl-2 restriction patterns over time. Changes in the bcl-2 gene restriction fragments were not observed. However, new immunoglobulin gene restriction fragments occurred frequently (30% of the cases studied). These new subclones must acquire a growth advantage to overgrow the original parent tumor. Thus, changes in the immunoglobulin gene restriction pattern serves as a marker for subsequent or coincident growth promoting mutations. We have begun to investigate potential second events which could impart a selective growth advantage to a lymphoma cell which would manifest itself as histologic or clinical progression. To this end, we are currently analyzing the potential role of several oncogenes and anti-oncogenes in a large series of progressed lymphomas. we are studying the involvement of the c-myc gene and have found new rearrangements of this proto-oncogene in 10-15% of the progressed lymphomas. The molecular structure of c-myc rearrangement in these secondary high grade lymphomas appears to be different from that seen in primary high grade lymphomas and we are currently studying these differences. We have found retinoblastoma gene abnormalities at the DNA and RNA levels in several different types of lymphomas at a lower incidence. We have also surveyed a large series of lymphomas with probes for several other genetic loci associated with disease progression and/or high grade histology (bcl-3, bcl-4), but have found only sporadic involvement of these loci. We have recently initiated investigations into the role of some members of the rel gene family and p53.